Targeting and drug delivery of therapeutics is becoming increasingly important especially with the use of cytotoxics in the treatment of cancer. A number of methods have been used to selectively target tumors with therapeutic agents to treat cancers in humans and other animals. Targeting moieties such as monoclonal antibodies (mAb) or their fragments have been conjugated to linear polymers via their side chain functional groups. However, this approach usually results in reduced receptor binding affinity either due to changes in the chemical properties of the antibodies or due to folded configuration of polymers that imbed the targeting moiety in the random coiled structure. Ideally, a new conjugate would encompass both a targeting functionality as well as a therapeutic value.
Recently, heterobifunctional polymeric conjugates having a targeting functional group on one end and a therapeutic moiety (e.g. a chemotherapeutic drug) on the opposite end has been disclosed, see US Patent Application 2002/0197261A1. The polymer conjugates employed have a polymeric spacer bonded to a polymeric carrier containing multiple side-chain functional groups that allow the attachment of multiple drug, molecules (e.g. poly(1-glutamic acid)) on one end, with the other end of the polymeric spacer bonded to a targeting moiety. However, the molecular weight of the polymeric spacer portion is considerably low.
Methods of preparing higher molecular weight heterobifunctional polymer constructs have been disclosed, see US Patent Application 2002/0072573A1. However, these methods involve the polymerization of monomers which in itself is not ideal due to undesirable polymer dispersity. Other previous methods have involved anionic ethoxylation and difficult purification steps. Attempting to achieve high molecular weight polymer substrates using the techniques above has resulted in poor quality and poor yield of desired product.
Due to the inadequacies of the present methods there exists a need for improved methods of making high molecular weight heterobifunctional polymer substrates that produce high yield and high purity substrates at the same time retaining low polymer dispersity. It would also be desirable to provide compounds incorporating heterobifunctional polymer substrates as a means of targeting and delivering therapeutically active compounds. The present invention addresses these needs.